Monoclonal antibodies (mAbs) play an important role in cancer chemotherapy. However, their activity is often not sufficient to produce a lasting benefit. Recent advances in antibody-drug conjugates (ADCs) allow to harness mAb specificity and target the delivery of a cytotoxic agent to the tumor with specific antigen expressed on the surface of a malignant cell, resulting in significant enhancement of both mAb and drug efficacies (Teicher B A. Current Cancer Drug Targets, 2009, 9, 982-1004). In an ADC, the highly potent cytotoxic agent is covalently linked to an antibody or antibody fragment. To achieve the effective therapeutic effects, all three components—antibody, linker and payload—play critical roles in defining target specificity, the degree of stability and mechanism of action and demanding criteria must be satisfied. Indeed, the in vivo stability and efficacy of ADCs can be improved by optimizing the linker and by selecting the appropriate antibody and payload.
Gemtuzumab ozogamicin (Mylotarg) was the first ADC approved in 2000 for the treatment of acute myelogenous leukemia (AML) but was then withdrawn from the market in 2010 because the post-marketing clinical trials failed to meet the prospective efficacy endpoint (Ricart A D. Clin Cancer Res. 2011, 17, 6417-6427). The second ADC, brentuximab vedotin (SGN-35, Adcetris), was approved on Aug. 19, 2011 under the accelerated conditions for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL) (Katz et al. Clin Cancer Res. 2011, 17, 6428-6436). However, significant side effects have been reported in patients receiving Adcetris treatment, with 31% of patients in clinical trials experiencing serious adverse events and 21% discontinuing the treatment due to adverse events. FDA added a black-boxed warning to Adcetris drug label that progressive multifocal leukoencephalopathy (PML) has been reported in Adcetris-treated patients. Other important warnings and precautions associated with Adcetris treatment include peripheral neuropathy, neutropenia, Stevens-Johnson syndrome and tumor lysis syndrome.
Thiol-maleimide chemistry is a commonly used method, whereby a cysteine residue, either native or engineered, for conjugation of mAb with cytotoxic agent. However, the thiol-succinimide adduct is known to undergo alkaline hydrolysis and retro-Michael addition. Particularly, the thiol-succinimide moiety in ADCs, when situated in the highly solvent-accessible sites, is susceptible to the exchange process with albumin, cysteine or glutathione as well as succinimide ring hydrolysis both in vitro and in vivo (Shen et al. Nat. Biotechonol. 2012, doi:10.1038/nbt.2108). The rapid dissociation of cytotoxic drug from the mAb, due to the maleimide exchange process, showed reduced target specific activity and increased liver toxicity in animal model. The instability of thiol-succinimide structure may have been the contributing factor in the serious adverse events associated with ADC treatment.